Mitochondrial DNA maintenance: an appraisal

Abstract

Mitochondria play a crucial role in a variety of cellular processes ranging from energy metabolism, generation of reactive oxygen species (ROS), and Ca(2+) handling to stress responses, cell survival, and death. Malfunction of the organelle may contribute to the pathogenesis of neuromuscular disorders, cancer, premature aging, and cardiovascular diseases, including myocardial ischemia, cardiomyopathy, and heart failure. Mitochondria are unique as they contain their own genome organized into DNA-protein complexes, so-called mitochondrial nucleoids, along with multiprotein machineries, which promote mitochondrial DNA (mtDNA) replication, transcription, and repair. Although the organelle possesses almost all known nuclear DNA repair pathways, including base excision repair, mismatch repair, and recombinational repair, the proximity of mtDNA to the main sites of ROS production and the lack of protective histones may result in increased susceptibility to oxidative stress and other types of mtDNA damage. Defects in the components of these highly organized machineries, which mediate mtDNA maintenance (replication and repair), may result in accumulation of point mutations and/or deletions in mtDNA and decreased mtDNA copy number impairing mitochondrial function. This review will focus on the mechanisms of mtDNA maintenance with emphasis on the proteins implicated in these processes and their functional role in various disease conditions and aging.

Neutrophil extracellular traps — the dark side of neutrophils

“…Mitochondrial DNA (mtDNA) has been described as a major source of neutrophil and eosinophil ETs (45)(46)(47). mtDNA is not organized in nucleosomes and is not associated with histones (48), which are essential structures of NETs. While NETs composed of mitochondrial DNA do not seem to be elicited from neutrophils in vivo (14), mtDNA may be important as a stimulus for NET formation.…”

Mitochondria and ageing: role in heart, skeletal muscle and adipose tissue

“…Excessive ROS formation causes detrimental effects on proteins and lipids, which induces cellular dysfunction and ultimately cell death. In addition, the proximity of the mitochondrial DNA to the site of ROS production in combination with the lack of protection of mitochondrial DNA by histones renders the mitochondrial DNA (mtDNA) highly susceptible to oxidative stress . Indeed, mice with a proofreading deficient mutant of the mitochondrial polymerase γ accumulate mutations in the mitochondrial DNA and have a reduced lifespan.…”

The role of mitochondria in cardiac development and protection

“…In contrast to the billions of base pairs long nuclear genome that has only two copies of most essential genes, mtDNA is only 16.5 kb and exists in hundreds to thousands of copies per cell, making selective degradation of mtDNA more cost efficient for the cell than its repair [94]. Nevertheless, an armory of mtDNA repair mechanisms do exist (reviewed in detail in [95,96]). As with the nuclear DNA repair mechanisms, the optimal strategy of mtDNA maintenance will depend on the nature of damage.…”